JP2010148870A - Biocompatible ceramic-polymer hybrid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a biocompatible material containing a biodegradable polymer included in the pores in a hydroxyapatite ceramic structure. <P>SOLUTION: The biodegradable polymer can be a poly L-lactic acid polymer. A method for preparing the biocompatible material includes: preparing a porous hydroxyapatite ceramic containing pores having an average pore diameter of 10 mm or larger; and forming a biodegradable polymer in the pores of the porous hydroxyapatite ceramic. The porous hydroxyapatite ceramic may be prepared by: preparing a slurry comprising hydroxyapatite fibers and heat-degradable particles in a selected solvent; filtering the slurry to obtain a paste and preparing a molded body obtained by compacting a body molded by using the paste; and heating the molded body to produce a porous hydroxyapatite ceramic structure. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

CROSS REFERENCE TO RELATED APPLICATIONS This invention claims priority from US Provisional Application No. 61 / 138,016, filed December 16, 2008, under 35 USC §119. The contents of the provisional application are all incorporated by reference.

TECHNICAL FIELD OF THE INVENTION The present invention relates to composite materials for bone repair or replacement, and more particularly to hybrid materials comprising hydroxyapatite and a biocompatible polymer.

Background of the Invention Many diseases, such as fractures, include damage to hard tissue (eg, bone). Such conditions require materials that can be used to repair the hard tissue damage. As the average lifespan increases, the material needs are expected to increase substantially.

  The material used for the repair is often required to have sufficient mechanical strength to replace the function of damaged hard tissue. These materials are used temporarily until the hard tissue itself is repaired or used as a permanent replacement. Various materials used for repairing the hard tissue include ceramic materials.

Recently, three types of ceramics have been used clinically for this purpose. Bioactive ceramics are materials that bond directly to the host bone. Examples of such materials include hydroxyapatite (Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ;
HAp). The second type is biodegradable ceramics. These materials can be gradually absorbed by the body. Examples of the biodegradable material include tricalcium phosphate (Ca ₃ (PO ₄ ) ₂ ; abbreviation is TCP). The third type of bioceramics is a bioinert ceramic. These materials are stable in vivo and have high mechanical strength. Examples of biologically inert ceramics include alumina (a-Al ₂ O ₃ ) and tetragonal zirconium (t-ZrO ₂ ).

Hydroxyapatite is a natural component present in teeth and bones in the human body.
Therefore, hydroxyapatite (HAp) is a suitable material candidate for hard tissue replacement or repair because of its excellent biocompatibility. Indeed, it is usually used as a filler to replace damaged bone or as a coating that promotes bone growth on the implant. For example, some medical implants such as hip joints and dental implants have been found to be coated with hydroxyapatite to promote bone formation on these implants.

Due to these favorable properties of hydroxyapatite, the development or improvement of this material for medical applications has received much attention. Various methods have been disclosed for modifying hydroxyapatite and other implants to improve their bone attachment and other properties. For example, it has been shown that the method of coating this material with bone morphogenetic proteins can improve cell attachment and subsequent binding to tissue. See Zeng, H., et al., Biomaterials 20 (1999): 377 384. Another commonly used modification is nitridation. Nitride formation improves the hardness of the hydroxyapatite and improves the chemical stability of the hydroxyapatite to the biological environment. Habelitz, S., et al., J. European Ceramic Society 19
(1999): 2685 2694, and Torrisi, L., Metallurgical
See Science and Technology 17 (1) (1999): 27 32.
Zeng, H., et al., Biomaterials 20 (1999): 377 384 Habelitz, S., et al., J. European Ceramic Society 19 (1999): 2685 2694, and Torrisi, L., MetallurgicalScience and Technology 17 (1) (1999): 27 32

  More recently, according to U.S. Pat.No. 7,211,271 issued to Risbud et al., These two methods (i.e., nitriding) are used to produce hydroxyapatite that promotes tissue growth on the material. And the formation of bone and bone morphogenetic proteins or analogues thereof, or coating with DNA encoding the aforementioned proteins or analogues thereof).

  Hydroxyapatite materials and modified hydroxyapatite materials have excellent biocompatibility and have beneficial tissue / bone formation promoting effects, but their mechanical properties, especially toughness value and Young's modulus, They are quite different from those of bones. As a result, the use of hydroxyapatite for bone repair or replacement creates undesirable stresses around the joint between these artificial materials and living bone. The undesired stress will eventually break the connection. Therefore, in addition to the advantages of hydroxyapatite, there is a need for new materials that are more similar to the mechanical properties of living bones.

SUMMARY OF THE INVENTION One aspect of the present invention relates to a hydroxyapatite ceramic hybrid material. The hydroxyapatite ceramic hybrid material according to one embodiment of the present invention includes a hydroxyapatite ceramic structure having pores, and includes a biodegradable polymer contained in the pores of the hydroxyapatite ceramic structure. The pores occupy 40-70% of the volume of the hydroxyapatite ceramic structure. In one embodiment of the present invention, the biodegradable polymer is a poly L-lactic acid polymer formed by an enzymatic polymerization reaction using a lipase as a catalyst.

  Another aspect of the invention relates to a method for preparing a hydroxyapatite ceramic material. A method according to an embodiment of the present invention includes a step of preparing a porous hydroxyapatite ceramic including pores having an average pore diameter of 10 mm or more, and a biodegradable polymer in the pores of the porous hydroxyapatite ceramic. Forming a step. The porous hydroxyapatite ceramic comprises preparing a slurry in which hydroxyapatite fibers and thermally decomposable particles are suspended in a selected solvent, filtering the slurry to form a paste, Forming into a mass using a paste, compressing the shaped mass to prepare a generated shape, and said generated shape at at least 1000 ° C. to prepare a porous hydroxyapatite ceramic structure Is prepared by the step of heating.

  Other aspects and advantages of the invention will be apparent from the following description and the appended claims.

FIG. 1 shows a conventional hydroxyapatite implant in the spine illustrating bone depression. FIG. 2 shows a flow chart illustrating a method for preparing porous hydroxyapatite ceramics according to one embodiment of the present invention. FIG. 3A shows a porous HAp ceramic prepared without using carbon bead inclusions. FIG. 3B shows a porous HAp ceramic prepared according to one embodiment of the present invention using inclusions of carbon beads having a diameter of 150 mm. Figures 4a-4d show the pore size distribution of HAp ceramics prepared using various carbon beads of different diameters. FIG. 5 shows a flow chart illustrating a method of forming a polymer in the pores of a porous HAp ceramic according to one embodiment of the present invention. FIG. 6 shows the microstructure of the HAp and PLLA hybrid material according to one embodiment of the present invention. FIG. 7 shows the porosity of various HAp and PLLA hybrid materials according to one embodiment of the present invention. FIG. 8 shows the bending strength and Young's modulus of various HAp-PLLA hybrid materials of the present invention. FIG. 9 shows the morphology of cells cultured for 7 days on the HAp-PLLA hybrid material described above, according to one embodiment of the present invention. In addition, high-density HAp ceramics was used as a positive control, and polystyrene for cell culture plates was used as a control. 10 (A) -10 (D) shows a porous ceramic structure (FIGS. 10 (A) and 10 (C)) called Apaceram (registered trademark) and the bipolar porous structure of the present invention. HAp ceramics (Fig. 10 (B) and Fig. 10 (D)) on rabbit tibia for 4 weeks (Fig. 10 (A) and Fig. 10 (B)) and 24 weeks (Fig. 10 (B) and Fig. 10 (D) )) Bone cell growth when implanted.

Aspects of the invention relate to bioceramic materials based on HAp having biological activity. Bioactive hydroxyapatite materials according to embodiments of the present invention have some mechanical properties similar to those of bone. Some embodiments of the invention relate to HAp and poly-L-lactic acid (PLLA) hybrid materials. The mechanical strength and Young's modulus of these HAp-PLLA hybrid materials are closer to those of living bone than HAp. In addition, PLLA is biodegradable and can be absorbed by the body, creating a space for new bone growth.
Some aspects of the invention relate to methods of preparing and using these hybrid materials.

As explained above, the mechanical strength and physical properties of hydroxyapatite (HAp) are very different from those of living bone. As shown in Table 1 below, it has a Young's modulus greater than that of living bone, but has a fracture toughness value lower than that of living bone. Therefore, hydroxyapatite is more susceptible to brittle fracture than living bone.

  Hydroxyapatite is less flexible and more easily broken, so when HAp is used for bone replacement or repair, abnormal stress is generated at the bone-HAp interface. The stress generates a joint surface that deteriorates over time, or the stress is a biological response that results in bone loss around the stress-generating joint surface (e.g., bone remodeling). It can even trigger the promotion of bone resorption by imbalance. As a result, the bone replacement does not function properly over time. For example, FIG. 1 shows an example in which a hydroxyapatite piece is used as a spacer in the spinal column. With the passage of time, the bone and HAp joints deteriorate and bone depression occurs.

In order to overcome the above problems, it is desirable to develop HAp ceramic materials having properties similar to those of living bone. In this regard, the inventors of the present invention have already reported that the properties of porous HAp can be changed by including other materials in the pores of the HAp structure. For example, when polymethyl methacrylate (PMMA) is introduced into porous HAp, the above hybrid has a Young's modulus of ~ 63 GPa, a fracture toughness value of ~ 2 MPa · m ^-1 , and a bending strength of ~ Reported to be 65 MPa. Aizawa
et al., Bioceramics, vol. 12, p. 453 (1999); and Aizawa et al., Key Engineer. Mater, vol. 218-220, p.465-468 (2002). PMMA showed relatively good resistance in vivo, but because PMMA is not biodegradable, the pores of HAp ceramics remain permanently blocked.

  Some embodiments of the present invention relate to porous HAp ceramics comprising a biodegradable polymer. Such hybrid materials have desirable mechanical properties similar to living bone. In addition, the biodegradable polymer is degraded and absorbed, creating a new bone growth space.

  FIG. 2 shows a flow chart illustrating the method of the present invention for preparing a hybrid consisting of HAp and a biodegradable material. In this example, the biodegradable material is poly-L-lactic acid (PLLA). However, one skilled in the art will recognize that other suitable biodegradable materials can be used instead.

As shown in FIG. 2, a slurry containing HAp fibers and carbon beads is prepared (step 21). The above-mentioned HAp fiber was developed by Kawata et al., “Development
of porous ceramics with well-controlled porosities and pore sizes from apatite
fibers and their evaluations, ”Journal of Materials Sciences: Materials in
It can be prepared by following the disclosure of medicine, Vol. 15, pp. 817-823 (2004). This paper is referred to as “Kawata paper” in the following description of this specification.

For example, if HAp fiber is Ca (NO ₃ ) ₂ (0.167 mol · dm ^-3 ), (NH ₄ ) ₂ HPO ₄
(0.1 mol ・ dm ^-3 ), (NH ₂ ) ₂ CO (0.5
mol · dm ⁻³ ), and HNO ₃ (0.1 mol · dm ⁻³ ). This solution contains Ca / P at a rate of 1.67. This solution is heated at 80 ° C. for 24 hours, and then heated at 90 ° C. for 72 hours to prepare an apatite fiber having a major axis diameter of about 60-100 mm. These fibers are collected, for example, by filtration. To prepare the suspension, the apatite fiber is suspended in water at an appropriate concentration (eg, about 1% by weight).

  The carbon beads in the slurry are replaced with any thermally decomposable particles. The thermally decomposable material (eg, carbon beads or plastic beads) will create a space between the fibers. After heat treatment, these materials will disappear inside the ceramic and move behind the pores. For clarity of description, the use of carbon beads as an example of the degradable material will be described below. However, those skilled in the art will understand that other similar degradable materials (eg, plastic beads, etc.) that can disappear from the pores within the ceramics may also be used. Carbon beads are commercially available. For example, Nikabeads® are available from Nippon Carbon Co., Ltd. (Yokohama, Japan) in various diameters (5, 20 or 150 mm).

  As shown in the Kawata paper, the size of the carbon beads ultimately affects the size of the ceramic pores. For use with embodiments of the present invention, use carbon beads (or thermally decomposable material beads) having an average diameter of about 10-500 mm, preferably about 100-200 mm, and most preferably about 150 mm. Can do.

  Furthermore, the amount of the carbon beads per amount of the HAp fibers ultimately affects the total porosity of the ceramic. According to embodiments of the present invention, the ratio of carbon beads to HAp used is 1/10 to 50/10 (w / w), preferably 2/10 to 10/10, and most preferably about 5/10.

  Since the carbon beads and the HAp fiber have different densities and are separated in the slurry, it is desirable to add another component that uniformly disperses these two components. For example, agar with an appropriate concentration (for example, 1/10 of the amount of the apatite fiber) is used. By using agar, the fibers and carbon beads are well dispersed and finally the pore distribution in the three-dimensional ceramic structure is uniform (random). Without the use of agar (or similar suspension aids), the fibers tend to condense into sheet (two-dimensional) structures. The slurry containing agar is warmed to a somewhat higher temperature (eg, a water bath) to dissolve the agar. Those skilled in the art will understand how to optimize the amount of agar and the temperatures used without undue experimentation. In addition, materials other than agar may also be used if materials other than agar facilitate uniform distribution of the HAp fibers and the carbon beads and are degraded at high temperatures.

  A solvent (for example, an alcohol such as ethanol) is added to the slurry (either the apatite slurry or the apatite-agar slurry) in order to promote the dispersion of the particles by changing the surface tension of the aqueous solution. You may add arbitrarily. The amount of the solvent will depend on the desired effect. For example, when ethanol is used, ethanol may be used in an amount of about 10-50% (v / v), preferably about 30% v / v, with respect to the total amount (water and ethanol combined). Good.

  The slurry is used to prepare the resulting shape that is sintered (heated at high temperature) to prepare the desired ceramic. For example, the slurry is poured into a mold of the desired shape in order to prepare a precursor of the generated form. Since the mold is porous and has a bottom surface through which the solvent can penetrate, the solvent (water and ethanol) can be removed by suction filtration if necessary. In addition to the above, as mentioned above, the mixed slurry containing HAp fibers and carbon beads can be made uniform by adding the desired amount of agar to the slurry. In the slurry, agar helps to create uniformly distributed (random) pores in a three-dimensional ceramic structure.

  The precursor of the product form is dried. It is then further compressed by applying a selected pressure of, for example, about 10-50 MPa, preferably about 20-40 MPa, more preferably about 30 MPa to prepare the resulting form (step 23). The compressing step affects the pore size in the final product ceramic and also affects the mechanical strength of the final ceramic product.

  Next, the obtained shaped body is sintered (for example, heating at a high temperature) to prepare the ceramic (step 24). The sintering (heating) step may be performed according to conventional procedures. The heating step may be performed at about 1000-1500 ° C, preferably about 1200-1300 ° C. The sintering step may be performed in an electric furnace. Furthermore, according to an aspect of the present invention, the heating step may be performed in a steam atmosphere in order to prevent the disappearance of hydroxyl groups from the hydroxyapatite. The time required for the sintering (heating) step will depend on the size of the generated features, the temperature used and other conditions. Typically, the curing step may take several hours, for example 1-10 hours, preferably about 3-5 hours.

  In the heating (curing at high temperature) step, the HAp fibers are bonded by sintering to become ceramics, and at the same time, the carbon beads are evaporated. As a result, the final HAp structure has relatively large pores (as described above) along with small pores formed by gaps between the fibers (carbon beads have not been incorporated into the generated features). Carbon beads were present). Therefore, these procedures prepare HAp structures in which two types of pores (ie, large and small pores) are distributed.

  For example, when carbon beads having a diameter of about 150 mm are used, pores of about 100 mm or larger are detected in the HAp ceramic. In addition to these pores, the resulting HAp ceramics also contain smaller pores with a diameter of about 1-5 mm resulting from gaps between the HAp fibers that do not contain the carbon beads. That is, these porous HAp ceramics have pores with two different size distributions, one group of small pores about a few micrometers in size and another group of pores of a size larger than 100 μm. Actually have. This is called HAp ceramics with a bipolar porous structure.

  As shown in the left panel (A) of FIG. 3, HAp ceramics were prepared without the addition of carbon beads. As a result, the pores are small in size in the range of a few mm (eg 1-5 mm). As shown in the right panel of Fig. 3 (B), the HAp ceramic prepared by adding carbon beads (diameter of 150 mm) is more in addition to the small pores (1-5 mm). Has large pores (up to 100 mm or larger pores). These pores are referred to as macropores and micropores, respectively, in FIG.

  As specifically mentioned in the Kawata article, the total porosity of the ceramic preparation can be controlled by varying the carbon bead size and the ratio of the amount of carbon beads to the amount of HAp. In addition to the carbon bead size and the amount used, the compacting pressure used in the preparation of the resulting shape and the sintering temperature used in the preparation of the ceramics also affect the total porosity of the final product. To do. Of these factors, the carbon bead diameter has the greatest influence on the final pore size. In contrast, the compression pressure and the sintering temperature have a relatively small effect on the final pores of the ceramic.

  According to an embodiment of the invention, the HAp ceramic has a total porosity of about 30-80%, preferably 40-70%. By using carbon beads, these ceramics have large interconnected pores. These interconnected pores are desirable to include the biodegradable polymers described above, and are also desirable for new bone growth when used in vivo.

  The percentage of porosity will affect the physical strength and mechanical properties of the ceramic. Therefore, lesser carbon beads are used if stronger or harder ceramics are desired. On the other hand, if a more flexible ceramic or a ceramic with a large total pore volume is desired, a larger amount of carbon beads is used.

  FIG. 4 shows the pore size distribution and pore volume of HAp ceramics prepared with various sized carbon beads. As shown in FIG. 4, panel (a), when carbon beads are not included, the prepared ceramics have the smallest pores (the median pore diameter is 1.2 mm because the pores originate from the gaps between the fibers). ). When carbon beads (5 mm) are included, the prepared ceramics will have two sizes of pores (panel b: median pore diameter is 2.5 mm) carbon beads (20 mm) The above prepared ceramics have larger pore size pores (Panel b: Median pore diameter is 2.6 mm.) Figure 4, Panel (d) is 150 mm It shows that the ceramics prepared using diameter carbon beads have medium diameter pores of 5.4 mm. However, these ceramics have two different pore sizes, one of which has a pore of less than 10 mm and the other clearly shows a pore diameter distribution between 10 and 100 mm.

  As noted previously, the porous HAp ceramic prepared by including carbon beads (eg, 150 mm in diameter) has large pores with a diameter on the order of ~ 100 mm. The large-sized pores generate many communication holes in the porous HAp ceramic. According to the aspect of the present invention described below, the communication hole is desirable. This is because the communication hole promotes the inclusion of a biodegradable polymer in the ceramic. In addition, these communication holes also assist in the formation of bone tissue within the ceramic after the device is implanted in a patient.

  The ceramic preparation is further processed (eg, cut or polished) to prepare the final desired ceramic product. The aforementioned further processing steps prepare a ceramic product in the form for the intended use.

  Referring again to FIG. 2, according to an embodiment of the present invention, the HAp porous ceramic is made by including one or more biodegradable materials in the pores (especially the communicating holes formed by these pores). Further processing is performed (step 25). Examples of suitable biodegradable materials include esters or amides. According to an embodiment of the invention, the biodegradable material is preferably an ester. More preferably, said biodegradable material is an ester of a natural acid such as L-lactic acid, glycolic acid, citric acid. The biodegradable polymer may also be prepared from a mixture of these materials such as, for example, a mixed polymer of lactic acid and glycolic acid. In the following description, poly-L-lactic acid ester is used as an example of the biodegradable material. However, those skilled in the art will recognize that any suitable biodegradable material known in the art can be used in embodiments of the present invention.

  According to some embodiments of the present invention, the polylactic acid ester is incorporated into the pores of the porous HAp ceramic by an enzyme that catalyzes the reaction of polymerizing the lactic acid. Any suitable enzyme, including lipase, can be used for the polymerization reaction. Suitable lipases include lipase CA, lipase PS or any suitable lipase. Several lipases such as Amano lipase PS produced by Burkholderia cepacia available from Sigma-Aldrich (St. Louis, MO) are commercially available.

Polymerization of the lactic acid (or its dimer lactide) using, for example, a lipase (eg, lipase S) enzyme is known in the art. For example, H. Uyama,
See K. Takeya, S. Kobayashi, Bull. Chem. Soc. Jpn., 68, 56 (1995). According to embodiments of the present invention, PLLA formation can use any protocol and can be performed under any suitable conditions. For example, FIG. 5 shows a flow chart illustrating one method of polymerization of lactic acid inside the pores of HAp ceramics according to one embodiment of the present invention. As shown in FIG. 5, the HAp, lactic acid (or lactide) and lipase are mixed in a reaction vessel (step 51).

  The substrate and enzyme mixture may be mixed in a solvent (eg, buffer) suitable for the selected lipase. In another method, the porous HAp ceramic may be separately filled with the substrate (eg, lactide) solution and the enzyme solution. For example, first immerse the enzyme solution in the HAp ceramic and then dry it after some time for the enzyme to bind to the surface of the ceramic pores (or from the pores to the Remove the solution.). Next, the obtained ceramic is immersed in a solution containing the substrate (for example, lactide).

  The gas is removed from the mixture by freezing and thawing and vacuuming twice or three times (step 52). The step of removing the gas is to ensure that air trapped in the pores inside the ceramic is removed and replaced with the reaction solution. Next, an inert gas such as nitrogen or argon is blown over the reaction solution (step 53). In order to easily perform the operation of the freeze-thaw-evacuation cycle, the outlet provided with a valve for easily discharging the gas (and subsequent reaction) and discharging the inert gas. May be carried out in a reaction vessel in which is installed.

  The polymerization can then proceed by maintaining the reaction mixture at an appropriate temperature for a selected time that depends on the enzyme and the reaction conditions used. Commercial suppliers of such lipases often recommend the conditions used for the reaction. This recommendation and experiment to improve the efficiency of the particular reaction may be followed. Such reaction optimization is a commonly known practice in the art.

  In some experiments, the PLLA polymerization reaction was carried out using lactide and lipase for a selected time (eg, 168 hours) at a temperature higher than 100 ° C. (eg, 130 ° C.). At this high temperature, the system is under pressure because it is the sealed reaction vessel. This high pressure may help to push the reaction solution into the pores of the ceramic. Under this reaction condition, the enzyme may not be stable for a long time. Not only that, the present inventor has found the above-mentioned high temperature conditions for good polymerization. While the actual mechanism is not known, it is possible that some or most of the polymerization may occur without catalysis by the enzyme under the reaction conditions. For example, the lipase in the system could catalyze the reaction at the start of the reaction. Once the lactide molecule begins to polymerize, each molecule generates a free hydroxyl group that can react with another lactide molecule in turn. Therefore, the polymerization reaction may proceed like a chain reaction even after the lipase loses activity at high temperature.

  After the polymerization reaction, the excessively formed PLLA is removed (step 55). The HAp-PLLA hybrid may then be polished to provide the final product (step 56). Note that the method shown in FIG. 5 is exemplary only. One skilled in the art will recognize that other variations or modifications of this procedure are possible within the scope of the present invention.

  The porous HAp having a biodegradable polymer (eg, poly-L-lactic acid (PLLA)) contained in the HAp comprises the HAp ceramic portion and the biodegradable material (eg PLLA) portion. It is a hybrid material. As shown in FIGS. 6 and 7, PLLA fills the pores of the HAp ceramics, so that the cross-sectional view of the resulting hybrid changed from a porous form to a dense structure. In these figures, PHA (−) means HAp ceramics to which no carbon beads were added in the preparation process, and PHA (150) means that carbon beads having an average diameter of 150 mm were added. In addition, PLLA (x%) means x% of the lipase used in the polymerization of PLLA (as 100% proportional to the amount of lactic acid in lactide).

  FIG. 6 shows scanning electron microscope (scanning EM) photographs of various ceramics (without PLLA) and hybrids (with PLLA). As shown in the left panel of FIG. 6, PHA (−), a HAp ceramic prepared without adding carbon beads, contains only small pores (resulting from entanglement of HAp fibers) (see also FIG. 3). I want to be.) In contrast, PHA (150), a HAp ceramic prepared by adding carbon beads (diameter 150 mm) to HAp fiber, has large pores (approximately 100 mm in size) and small pores (approximately several mm in diameter). Have both.

  As shown in the right panel of FIG. 6, 3% lipase (proportional to the amount of lactic acid in lactide) was used to form biodegradable material (ie, PLLA) in the pores, followed by PHA (- ) / PLLA (3%) hybrids indicate that most of the pores are filled with PLLA, as evidenced by the smooth cross-section of the microscope photo. Similarly, the PHA (150) / PLLA (3%) hybrid does not have large pores (right panel in FIG. 6), and its cross-sectional area is almost smooth, so PLLA is inside the large pores. Indicates that it is formed efficiently. In both cases, there are only remaining small pores that are not completely filled.

  FIG. 7 is a graph showing the quantitative results of the filling state by PLLA in the ceramic pores. From the chart above, the HAp ceramics prepared without adding carbon beads has a total porosity of about 38%, whereas those prepared with 150 mm carbon beads added are about 70%. It became clear that the porosity was. After the formation of PLLA in the pores, approximately 5-7% of the pores remain in all the hybrid materials. This result suggested that the 5-7% remaining pores were common to all ceramics, regardless of the method by which they were prepared. Furthermore, the results show that PHA (150) ceramics also have only 5-7% residual pores, so that all the large pores of the PHA (150) ceramics are completely filled with PLLA. It is suggested. The results shown in FIG. 7 also suggest that there is no significant difference even if the polymerization reaction is carried out with 1% or 3% lipase.

  Compared to HAp ceramics or HAp-PLLA hybrids with small pores, the mechanical or physical properties of HAp ceramics or HAp-PLLA hybrids with large pores are expected to have changed significantly. As shown in FIG. 8, the bending strength and Young's modulus of HAp with large pores are much smaller than those without large pores. Due to the formation of PLLA, the bending strength and Young's modulus increase in both HAp ceramics with small pores and HAp ceramics with large pores. Even if the polymerization is carried out with 1% or 3% lipase, there appears to be no significant difference.

  From the results shown in FIG. 8, it is clear that the bending strength and Young's modulus of HAp ceramics with large pores are improved by PLLA formation, and they can be made very close to the physical properties of the above-mentioned living bone Indicated. The inventors have found that the large pores in the HAp ceramics are important for inducing bone growth inside the ceramics (see description for FIG. 9). However, due to the presence of large pores in the HAp ceramics, the physical strength of the HAp ceramics is significantly reduced as compared with the HAp ceramics that do not have the large pores. Therefore, PLLA introduction formation is a practical approach to improve the usefulness of the HAp ceramic material.

  The low flexural strength and Young's modulus of HAp-PLLA hybrids with large pores according to embodiments of the present invention make these materials more compliant than HAp with small pores. As an application of the HAp-PLLA hybrid material having these large pores, an application in which new bone formation is desired can be considered. Therefore, the low physical strength of these materials will only show a temporary effect. This new difference in mechanical properties will disappear once new bone growth is achieved. More importantly, the hybrid with large pores can promote the ingrowth of bone cells (eg, osteoblasts) within the interconnected large pores. Therefore, the HAp-PLLA hybrid with large pores will be applied to situations where new bone formation is required.

  As shown in FIG. 8, in all cases (HAp ceramics having large pores or HAp ceramics having small pores), when PLLA is introduced, the mechanical strength of the ceramic materials (for example, bending strength and Young's modulus) ) Increases due to two or more factors. These results demonstrate the concept of using biodegradable materials to change the mechanical properties of HAp ceramic materials. Furthermore, from these results, desirable binding of properties can be achieved by controlling the size of the pores and / or the extent of biopolymer formation. For example, while maintaining the mechanical properties of the HAp-PLLA hybrid material in the physical properties of the living bone, for example, using smaller carbon beads (eg, 20, 50 or 100 mm diameter) to enter the bone Porous ceramics with smaller pores that are sufficiently large may be prepared.

  The HAp-PLLA hybrid material described above incorporates the desirable biocompatibility of HAp and biodegradability of PLLA. These materials are expected to have very high biocompatibility when used in vivo, and the biodegradable PLLA can be altered by the advancement of bone cells such as osteoblasts That is expected. Therefore, these materials are expected to assist in the formation of new bone tissue in the pores of the hybrid material.

In order to test the biocompatibility and usefulness of the HAp-PLLA hybrid material of the present invention, together with MC3T3-E1 cells derived from mouse skulls and well characterized as osteoblast-like cells, These materials were incubated. The incubation was carried out in a-MEM culture medium containing 10% fetal calf serum at 37 ° C. in a 5% CO ₂ atmosphere. Briefly, a piece of the hybrid material (about 15.5 mm in diameter and 1-1.5 mm in thickness) is incubated with 3.0 × 10 ⁴ MC3T3-E1 cells for several days. Monitored. The material was removed at a predetermined time, and the cell growth and attachment over time were observed by scanning EM.

  As shown in FIG. 9, the HAp-PLLA hybrid material according to the embodiment of the present invention can induce cell growth on its surface very well. At 7 days, the cells are proliferating well on these materials. From this SEM observation, although it could not be clearly found, it seems that PLLA is partially dissolved, and as a result, cells are proliferating while moving into the formed space. These results indicate that the HAp-PLLA hybrid materials of the present invention are non-toxic to the cells described above, and that they have been found to promote the growth of osteoblast-like cells. Therefore, the HAp-PLLA hybrid material of the present invention would be useful for bone repair and replacement.

  To further test the usefulness of these materials in bone repair and replacement in vivo, these porous ceramics were embedded in rabbit tibia. In these experiments, each of the three rabbits was used to compare the commercially available ceramic Apaceram® (obtained from Pentax Corp. Japan) with the porous ceramic of the present invention. . Apaceram® is a biocompatible hydroxyapatite.

FIG. 10 (A) (Apaceram®) and FIG. 10 (B) (150 mm carbon beads, PHA (150), which are the results after 4 weeks from embedment. As shown by dark blue staining with toluidine, both ceramics show signs of new bone formation, as shown in HAp ceramics with a porous structure.
FIG. 10 (C) (Apaceram (registered trademark)) and FIG. 10 (D) (bimodal porous HAp of the present invention) are the results after 24 weeks.
From these results, in the property of promoting bone formation, that is, the property of promoting the formation of new bone in the large pores of HAp having the bipolar porous structure of the present invention, HAp with a structure has been shown to be equivalent or superior to existing commercially available biocompatible ceramics (Apaceram®).

  The excellent properties of HAp with a bipolar porous structure of the present invention is that the large pores are interconnected, which will further promote the growth of bone cells inside the ceramic. Probably due to the fact. At the same time, the smaller pores may facilitate the release of nutrients to the cells.

  Advantages of aspects of the invention may include one or more of the following points. The bipolar porous structure of the HAp ceramic of the present invention includes large pores that form interconnected channels. These internally connected channels promote the formation of biopolymers within the channels. More importantly, these interconnected channels aid bone growth inside these ceramics. The presence of large pores in HAp ceramics significantly changes the physical properties of these materials. However, by forming PLLA polymer (or other biodegradable polymer) inside these porous HAp ceramic materials, the physical properties of the porous HAp ceramic materials are greatly improved, These materials are given with similar mechanical properties. Therefore, when these hybrid materials are used for bone repair or replacement, they will not induce much stress on their interface. In vivo studies have shown that these HAp-PLLA hybrid materials are non-toxic to the cells and actually promote the growth of bone cells (eg, osteoblasts).

  Although the present invention has been described with respect to a limited number of embodiments, those skilled in the art who have the benefit of the disclosure herein will recognize other embodiments without departing from the scope of the invention disclosed herein. You will recognize that you can devise. Accordingly, the scope of the invention should be limited only by the attached claims.

Claims (19)

Hydroxyapatite ceramic hybrid material,
A hydroxyapatite ceramic hybrid material comprising a hydroxyapatite structure having pores therein and a biodegradable polymer contained in the pores of the hydroxyapatite ceramic material.   2. The hydroxyapatite ceramic hybrid material according to claim 1, wherein the biodegradable polymer is a poly L-lactic acid polymer.   2. The hydroxyapatite ceramic hybrid material according to claim 1, wherein the biodegradable polymer is a polyglycolic acid polymer.   2. The hydroxyapatite ceramic hybrid material according to claim 1, wherein the biodegradable polymer is a mixed polymer containing L-lactic acid and polyglycolic acid.   2. The hydroxyapatite ceramic hybrid material according to claim 1, wherein the pores include two kinds of pore size distributions, one of which has an average size of 10 mm or more.   2. The hydroxyapatite ceramic hybrid material according to claim 1, wherein the pores occupy 40-70% as a volume of the hydroxyapatite ceramic structure. A method for preparing a hydroxyapatite ceramics-polymer hybrid material comprising:
Preparing a porous hydroxyapatite ceramic comprising pores having an average pore diameter of 10 mm or greater, and forming a biodegradable polymer in the pores of said hydroxyapatite ceramic.   8. The porous hydroxyapatite ceramic comprises two groups of pores, one group having an average pore size of 5 mm or less and the other group having an average pore size of 10 mm or more. the method of.   The method of claim 7, wherein the biodegradable polymer is a poly L-lactic acid polymer.   The method of claim 1, wherein the biodegradable polymer is a polyglycolic acid polymer.   The method of claim 7, wherein the biodegradable polymer is a mixed polymer comprising L-lactic acid and polyglycolic acid.   8. The method of claim 7, wherein a lipase is used in the step of forming the biodegradable polymer. Preparing a slurry comprising hydroxyapatite fibers and thermally decomposable particles in a solvent selected from the porous hydroxyapatite ceramics;
Filtering the slurry to obtain a paste;
Preparing a shaped mass using the paste;
8. The method of claim 7, wherein the forming is prepared by compressing the shaped mass to prepare a generated form and heating the generated form at a temperature greater than about 1000 ° C. for a selected duration.   14. The method according to claim 13, wherein the thermally decomposable particles are carbon beads.   14. The method of claim 13, wherein filtering the slurry and preparing the shaped mass is performed in a single step by filtering through a mold with a filter at the bottom of the mold.   14. The method of claim 13, wherein the heating is performed at about 1300 ° C.   14. The method of claim 13, wherein the slurry further comprises agar that aids in dispersing the hydroxyapatite fibers and the thermally decomposable particles.   14. The method of claim 13, wherein the heating is performed in the presence of steam.   The method of claim 13, wherein the carbon beads have an average diameter of about 150 mm.

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